Mini llama proteins show promise for Alzheimer’s treatment

"Camelid nanobodies open a new era of biologic therapies for brain disorders and revolutionize our thinking about therapeutics," says co-corresponding author Philippe Rondard of the Centre National de la Recherche Scientifique (CNRS) in Montpellier, France. "We believe they can form a new class of drugs between conventional antibodies and small molecules."

How Nanobodies Were Discovered

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

Antibody-based drugs are widely used to treat conditions like cancer and autoimmune diseases, but they have shown limited success in addressing disorders of the brain. Even the few antibody therapies that provide some benefit, such as certain Alzheimer's treatments, are often linked to unwanted side effects.

According to the researchers, nanobodies' compact structure gives them a distinct advantage. Their smaller size allows them to cross the blood-brain barrier and act on targets more efficiently, which could lead to improved outcomes 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 highly soluble small proteins that can enter the brain passively," explains co-corresponding author Pierre-André Lafon, also of CNRS. "By contrast, small-molecule drugs that are designed to cross the blood-brain barrier are hydrophobic in nature, which limits their bioavailability, increases the risk of off-target binding, and is linked to side effects."

Beyond their unique biological properties, nanobodies are simpler to produce and purify than traditional antibodies. They can also be precisely engineered and fine-tuned to target specific molecules in the brain.

Before nanobody-based drugs can be tested in human clinical trials, several key steps must be completed. The research team notes that toxicology studies and long-term safety assessments are essential. 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 accurate dosing strategies).

"Regarding the nanobodies themselves, it is also necessary to evaluate their stability, confirm their proper folding, and ensure the absence of aggregation," says Rondard. "It will be necessary to obtain clinical-grade nanobodies and stable formulations that maintain activity during long-term storage and transport."

Moving Toward Clinical Applications

"Our lab has already started to study these different parameters for a few brain-penetrant nanobodies and has recently shown that conditions of treatment are compatible with chronic treatment," Lafon adds.

This research was supported by the Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), University of Montpellier, French National Research Agency (ANR-20-CE18-0011; ANR-22-CE18-0003; ANR-25-CE18-0434), Fondation pour la Recherche Médicale (FRM EQU202303016470 and FRM PMT202407019488), LabEX MAbImprove (ANR-10-LABX-5301), Proof-of-concept Région Occitanie, and the transfer of Technology Agency SaTT AxLR Occitanie.