Blood–brain barrier model used to test antibodies

Researchers at Uppsala University have developed a simple yet effective artificial blood–brain barrier model that can be used to determine how well antibody-based therapies can enter the brain, and could reduce the need for animal testing in the future.

Protein-based biopharmaceuticals or biologics, such as antibodies, are promising therapeutic tools to specifically target clumps of protein found in neurodegenerative diseases such as Alzheimer’s and Parkinson’s. However, the blood–brain barrier (BBB) provides a significant hurdle when trying to deliver biologics to areas of the brain to stop these large molecules causing disease.

One of the most effective ways of delivering large antibodies into the brain is to piggyback existing pathways within the body that are designed to deliver essential molecules. Antibodies can be redesigned to essentially trick the BBB into thinking the antibody needs to enter the brain via an existing pathway. Animal experimentation is the most common method for testing whether an antibody can penetrate the BBB. However, aside from the cost in terms of time and money, there is an ethical requirement to reduce the number of animal experiments.

Greta Hultqvist’s research group at Uppsala has now developed an artificial BBB model that can be used to determine how well antibody-based therapies can enter the brain. Described in the journal Molecular Pharmaceutics, the model can be used in place of animal testing to validate the antibody’s ability to cross the BBB.

“There are many different cell culture-based BBB models published, but most try to mimic the complex functions of the BBB, making them harder to work with when compared to the artificial BBB model we have developed that primarily focuses on studying how biologics are transported,” said Uppsala’s Jamie Morrison.

“Our goal was to develop a robust and simple mouse cell culture model system, where multiple antibodies could be tested in a relatively short period of time. Our results show a clear distinction between antibodies that are able to cross the BBB and those that cannot. Our findings from the new model have been validated in mice.”

The research group has also developed a new in-house designed antibody that has been shown to have a better uptake into the brain compared to traditional antibodies. The antibody was tested using the artificial BBB model and later confirmed in mice studies. That antibody has been presented in the Journal of Neurochemistry.

“We validated the results using the artificial BBB model multiple times, but it was still somewhat surprising to see just how well the results mimicked what we saw when conducting brain uptake studies in mice using our antibody,” said Nicole Metzendorf, first author on the antibody study. “It was exciting to see a significant improvement in brain uptake using the new antibody format.”

Even though the artificial BBB model is new, it has already become ingrained in many of the new research projects within the research group. According to Morrison, “The assay will no doubt enhance the preclinical development of methods to deliver large antibody-based biologics across the BBB and into the brain, providing hope to those suffering from neurodegenerative disorders.”

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