Can Antibodies Cross the Blood-Brain Barrier?

By Ahmed Donia, Ph.D.Reviewed by Emily Henderson, B.Sc.

The human brain is considered to be the most complex organ in the human body, with 100 billion nerve cells making over 500 trillion nerve connections. The human brain also has serious security measures for protection.

Image Credit: decade3d - anatomy online/Shutterstock.com

The blood-brain barrier (BBB), which is one of these security measures, is a protective layer of cells that only permit specific substances to pass through it from the blood into the human brain. Antibodies do not normally cross the BBB to the human brain. But, recent studies report that engineered antibodies can cross the BBB thanks to recent developments in immunotherapy.

Why antibodies cannot cross the BBB

Antibodies have poor brain bioavailability, which limits their use for treating central nervous system diseases, either for active or passive immunotherapy. For entry to the human brain, antibodies must cross the BBB, which helps regulate the exchange of materials between the blood and the brain. Under normal circumstances, the BBB allows small lipophilic substances, ions, and water to smoothly pass through their concentration gradients.

Nutrients like amino acids and glucose enter the human brain through transporters. Larger molecules such as transferrin, leptin, and insulin enter via receptor-mediated transcytosis. Epithelial cells of the arachnoid membrane and choroid plexuses permit, in an indirect way, the movement of plasma-borne molecules to the cerebrospinal fluid (CSF) which bathes the cerebral exterior and interior surfaces of the parenchyma in the brain.

The concentration of IgG in the CSF is clinically calculated with a normal steady-state cerebrospinal fluid/serum ratio of 0.0027. Although there is limited protein transport through the blood-cerebrospinal fluid barrier, the choroid plexus tight junctions are notably more penetrable than the blood-brain barrier capillaries.

There is a limited exchange of large molecules between human brain cells and CSF so the IgG persists in CSF, making an insufficient evaluation of its bioavailability in the human brain. Very few researchers have studied the drug movement into the human brain due to technical reasons.

There is an urgent need to assess the brain bioavailability of therapeutic Ig as the clinical efficacy of drugs depends on the interaction with their targets. However, some in vivo studies determined the brain bioavailability of monoclonal or polyclonal Ig with both quantitative and qualitative studies.

Circumvent inaccessibility of antibodies.

Researchers suggested that new methodologies can be applied for the generation of antibody-based therapies for brain diseases. One of the most important features of antibodies is that they are highly specific.

However, researchers in industry and academia are aiming to design antibodies that have the ability to bind to more than one target. Watts and colleagues made a therapeutic antibody against the enzyme β-secretase 1, which is a popular Alzheimer’s disease drug target. They developed a method to enhance the amount of this antibody that entered the human brain.

The enzyme β-secretase 1 can process the amyloid precursor protein into amyloid-β peptides which include molecular species that could cluster to form the amyloid plaques present in Alzheimer’s brain patients. The enzyme β-secretase 1 inhibitors, which block the activity of β-secretase 1, decrease the synthesis of the aggregation-prone amyloid-β peptides, therefore lowering the formation of amyloid plaques and reducing the progression of Alzheimer’s disease.

Despite the fact that small-molecule inhibitors of the enzyme β-secretase 1 have been developed and can easily pass the blood-brain barrier due to their little sizes, they do not have good specificity and so could have harmful side effects. Watts and his team developed an anti- β-secretase antibody that bound to enzyme β-secretase 1 with high specificity and inhibited its activity. They found that this antibody can decrease the synthesis of aggregation-prone amyloid-β peptides in cultured primary nerve cells. They injected these antibodies into monkeys and mice, and found a continuous reduction in the amyloid-β peptide concentrations in the circulation of these animals and to a lower extent in their brains.

These engineered antibodies targeted also the transferrin receptors, which could activate a molecular channel that can import iron into the brain under normal conditions. The engineered antibodies clung to these transferrin receptors and were moved into the brain, where they work against β-secretase 1. These double-duty (double target) antibodies have very good results, with concentrations of amyloid-β dropping by 47%1 in the brain just one day after receiving a single injection of the antibody.

Another classical rule that has been defied is the high affinity between an antibody and its target. In a general way, the higher the binding affinity, the stronger the interaction. Therefore, most antibody engineers sought to design antibodies with the tightest binding and highest affinity.

Watts and Dennis began making engineered antibodies with high affinity against the transferrin receptors but found that these engineered antibodies stayed bound and locked within the blood vessels of the brain rather than penetrating its tissues. Then, they lowered the affinity of engineered antibodies, and they found that those modified antibodies were distributed more broadly in the brain. In other terms, the antibodies with low affinities get off and are widely distributed.

Further Reading

• All Antibodies Content
• What are Therapeutic Antibodies?
• What are Bispecific Antibodies?
• Creating a Nanobody Library with PCR
• Proving Monoclonality with PCR