Small llama proteins show promise in treating Alzheimer’s disease

“Gel nanobodies open a new era of biological treatments for brain disorders, revolutionizing our thinking about treatments,” says co-author Philippe Rondard of the Center National de la Recherche Scientifique (CNRS) in Montpellier, France. “We believe they could form a new class of drugs between traditional antibodies and small molecules.”

How were nanobodies discovered?

Nanobodies were first identified in the early 1990s by Belgian scientists who were studying the immune system of camelids. They found that in addition to the standard antibodies consisting of two heavy chains and two light chains, camelids also produce a simpler version consisting of only heavy chains. The small active portion of these antibodies – now known as nanobodies – is about one-tenth the size of a typical antibody. These unique molecules have not been observed in any other mammals, although they are found in some cartilaginous fish.

Antibody-based drugs are widely used to treat conditions such as cancer and autoimmune diseases, but have shown limited success in treating brain disorders. Even the few antibody treatments that provide some benefit, such as some Alzheimer’s disease treatments, are often associated with unwanted side effects.

According to the researchers, the compact structure of nanobodies gives them a distinct advantage. Its smaller size allows it to cross the blood-brain barrier and act on targets more efficiently, which may lead to improved results with fewer adverse reactions. In previous studies, nanobodies have been shown to restore normal behavior in mouse models of schizophrenia and other neurological disorders.

How nanobodies work in the brain

“These are small proteins that are highly soluble and can enter the brain passively,” explains co-author Pierre-André Lafon, also from the Center National de la Recherche Scientifique. “In contrast, small-molecule drugs designed to cross the blood-brain barrier are inherently hydrophobic, which limits their bioavailability, increases the risk of off-target binding, and is associated with side effects.”

In addition to their unique biological properties, nanobodies are easier to produce and purify than conventional antibodies. They can also be designed and fine-tuned to target specific molecules in the brain.

Before we can test nanobody-based drugs in human clinical trials, several key steps must be completed. The research team notes that toxicology studies and long-term safety evaluations are necessary. They also need to understand the effects of chronic administration and determine how long nanobodies remain active in the brain (a crucial step for developing precise dosing strategies).

“With regard to the nanobodies themselves, it is also necessary to evaluate their stability, ensure their correct folding, and ensure that there are no aggregates,” says Rondard. “It will be necessary to obtain clinical-grade nanobodies and stable formulations that maintain activity during long-term storage and transportation.”

Moving towards clinical applications

“Our lab has already begun studying these different agents for a few brain-penetrating nanobodies, and recently showed that the treatment conditions are compatible with chronic treatment,” Laffon adds.

This research was supported by the Center National de la Recherche Scientifique (CNRS), the National Institute of Health and Medical Research (INSERM), the University of Montpellier, the French National Research Agency (ANR-20-CE18-0011; ANR-22-CE18-0003; ANR-25-CE18-0434), the Foundation for Medical Research (FRM EQU202303016470 and FRM PMT202407019488), LabEX MabImprove (ANR-10-LABX-5301), Région Occitanie proof of concept, and SaTT AxLR Occitanie technology transfer.