Tiny antibodies cross the blood-brain barrier and improve memory: study

A team of Canadian and French researchers have shown for the first time that miniature antibodies, called nanobodies, can get into the brain and have beneficial effects on cognitive function.

The study, which was published in Nature, found that nanobody therapy improved memory and sensory processing in mouse models of schizophrenia and a rare neurodevelopmental disorder called GRIN1, highlighting the potential of this approach in treating brain diseases.

At one-tenth the size of an antibody, nanobodies are found in animals from the camelid family, which includes camels, llamas and alpacas.

Their small size makes it easier for nanobodies to get into places that are hard for antibodies to access, such as the complex structures of a protein or the brain.

“Nanobodies can do the same things as antibodies, but because they’re much smaller, they can get into little crevices and act like a drug,” says Amy Ramsey, an associate professor of pharmacology and toxicology at the University of Toronto’s Temerty Faculty of Medicine.

Ramsey co-led the Canadian team along with Ali Salahpour, a professor and chair of the department of pharmacology and toxicology at Temerty Medicine.

She explains that by fitting into a target protein’s unique 3-D shape, nanobodies can alter the protein’s function by gently fine-tuning it like a light dimmer. This makes nanobodies more similar to small molecule drugs with the advantage of having longer lasting effects, like those seen with antibody-based therapies.

In 2019, Ramsey and Salahpour were on sabbatical at the Institute of Functional Genomics at France’s Université de Montpellier, where researchers Jean-Philippe Pin, Julie Kniazeff and Philippe Rondard had developed a nanobody pair to target a protein receptor in the brain called mGlu2. Previous research suggested the mGlu2 receptor may be a good drug target for schizophrenia, and the French researchers were looking for a good model that they could use to test their nanobody.

As it happens, Ramsey’s lab had developed a mouse model of a rare human neurodevelopmental disorder called GRIN1 and the model shared a key characteristic with schizophrenia — lower levels of the NMDA receptor in the brain.

“The reduced NMDA signaling in this model is representative of a spectrum of disorders including schizophrenia and autism,” says Salahpour.

After confirming the nanobodies reached the brain, the researchers studied their effects on memory in two distinct mouse models — Ramsey’s GRIN1 model and a drug-induced model of schizophrenia. They found that in both models, the nanobody therapy improved memory, even seven days after the first dose. The treatment also enhanced sensory processing in the GRIN1 mouse model.

Led by senior research associate Tatiana Lipina, the researchers developed a long-term dosing strategy — a large initial dose followed by lower weekly doses — that maintained the beneficial effects of the nanobody therapy for more than four weeks. Ramsey notes this finding is particularly exciting because for many drugs, repeated dosing can often lead to tolerance and the drug becoming less effective.

Importantly, neither sex nor weight had any impacts on how well the treatment worked.  

“Nanobodies have a lot of promise to be complementary to traditional biologic therapies like antibodies,” says Ramsey.

“They might be able to do some things that traditional biologics cannot, like crossing the blood-brain barrier and acting to modulate a target.”

Building on this collaboration, she is working on a new project with the French team and other European researchers to investigate the effects of nanobodies in other mouse models of neurodevelopmental disorders, including models that have the exact same genetic variations as human patients.

As Ramsey and Salahpour prepare to head back to France for their next sabbatical, Salahpour reflects on the power of international collaborations.

“To do this type of comprehensive study, you need a lot of expertise from different angles. It speaks to the importance of multidisciplinary and collaborative borderless research.”

This research was supported by the Canadian Institutes of Health Research and the French National Research Agency.