In 2025, the European Medicines Agency approved two antibodies for Alzheimer's disease: lecanemab (Leqembi^TM, from Biogen) and donanemab (Kisunla^TM, from Eli Lilly and Company), both based on immunotherapy (the use of molecules from the immune system to treat diseases). These antibodies, obtained in the laboratory, act against the Aβ peptide, a protein fragment that accumulates in the brain of patients with Alzheimer's disease. The fact that the immune system eliminates this protein helps slow the characteristic cognitive decline of the disease.
These two antibodies are the first disease-modifying therapies for Alzheimer's. They stop and, in some cases, even partially reverse this devastating condition. However, a frequent and characteristic side effect of these drugs is cerebral bleeding, detectable by magnetic resonance. The brain does not have the molecules and cells that make up the systemic immune system, so the entry of antibodies into the brain is not desirable under healthy conditions, although it is necessary for these treatments to be effective. The incidence of bleeding in clinical trials ranged from 10 to 27% of treated patients, with a particularly high incidence in individuals carrying a specific apolipoprotein allele: the APOEε4 allele. In Europe, these treatments can only be administered to people with one or no copy of the APOEε4 allele, a genetic variant associated with a higher risk of Alzheimer's.
The Protein Design and Immunotherapy group at the UAB, led by the Chair Professor Sandra Villegas from the Department of Biochemistry and Molecular Biology, has been working for years with the hypothesis that full-length antibodies could be unsafe for the treatment of neurodegenerative diseases, since they recruit systemic immune system cells into the brain. This undesirable recruitment can disrupt the blood-brain barrier and cause bleeding.
“That is why we designed the monocatenary antibody fragment (scFv-h3D6) targeting the Aβ peptide, which does not have the region responsible for recruiting these immune cells, and we have broadly demonstrated its efficacy at the molecular, cellular and cognitive scale in mice”, says Professor Sandra Villegas.
Now, in collaboration with , Dr Silvia Lope-Piedrafita, a researcher from the UAB expert in magnetic resonance, and Dr Mar Hernández-Guillamon, a researcher from the Vall d’Hebron Research Institute expert in the APP23 mouse model, the group has used magnetic resonance imaging to visualize the bleeding caused by the full-length antibody bapineuzumab, from which the developed fragment derives, and compare it to the effects of administering only the antibody fragment. The results notably show that the bleeding does not occur when administering the antibody fragment, while therapeutic effects are maintained.
Therefore, concludes Professor Villegas, “the work shows that antibody fragments can offer a safer alternative than intact antibodies, which paves the way for new research into an effective and safe drug for Alzheimer's disease.”