Nanobodies—tiny proteins derived from animals in the camelid family including camels, llamas, and alpacas—could be useful in treating brain disorders like schizophrenia and Alzheimer's disease. In a paper publishing in the Cell Press journal Trends in Pharmacological Sciences on November 5, researchers explain why nanobodies' small size allows them to treat neurological conditions more effectively and with fewer side effects in mice and outlines the next steps towards developing nanobody treatments that are safe for humans.
"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 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."
Nanobodies were first discovered in the early 1990s by Belgian scientists who were studying the immune systems of camelids. The researchers found that in addition to making conventional antibodies, which are composed of two heavy chains and two light chains, camelids also produce antibodies with just heavy chains. The antigen-binding fragments of these antibodies—now known as nanobodies—are one-tenth the size of conventional antibodies. They have not been found in any other mammals, although they have been observed in some cartilaginous fish.
Therapeutic approaches for diseases such as cancer and autoimmune disorders often center around antibodies, but so far, antibody therapies have had limited efficacy in treating brain disorders. Also, the treatments that do show some therapeutic benefits, including a few drugs for Alzheimer's treatment, are often associated with secondary side effects.
With their much smaller size, nanobodies have the potential to offer better efficacy for brain diseases with fewer side effects, the authors say. In previous research, the team has shown that nanobodies can restore behavioral deficits in mouse models of schizophrenia and other neurologic conditions.
"These are highly soluble small proteins that can enter the brain passively," says 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."
Nanobodies are also easier than conventional antibodies to produce, purify, and engineer and can be fine-tuned to their targets.
The authors acknowledge that several steps need to be taken before nanobodies can be tested in human clinical trials for brain disorders. Toxicology and long-term safety testing are essential, and the effect of chronic administration needs to be understood. Pharmacokinetics and pharmacodynamics will also need to be studied to determine how long these molecules stay in the brain—a step that is important for developing dosing strategies.
"Regarding the nanobodies themselves, it is also necessary to evaluate their stability, confirm their proper folding, and ensure the absence of aggregation," Rondard says. "It will be necessary to obtain clinical-grade nanobodies and stable formulations that maintain activity during long-term storage and transport."
"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.
