A fragment of antibody avoids the typical haemorrhages of new treatments for Alzheimer's
Recently, two immunotherapeutic Alzheimer's treatments using full antibodies have been approved, but it is known that they can cause brain haemorrhages as a side effect. The UAB Protein Design and Immunotherapy Group is investigating an alternative to these drugs using an antibody fragment. The results show that it removes the Aβ peptide without causing haemorrhages and could be a safer and more effective option.
Department of Biochemistry and Molecular Biology
Protein Design and Immunotherapy Group
Universitat Autònoma de Barcelona
Immunotherapy refers to the use of molecules related to the immune system for the treatment of diseases. In the year 2025, two antibodies were approved by the European Medicines Agency (EMA) to treat Alzheimer’s Disease (AD): lecanemab (LeqembiTM, Biogen) and donanemab (KisunlaTM, Eli Lilly and Co). Such antibodies are obtained in the laboratory and are directed against a fragment of a protein that accumulates in the brain of AD patients, the Aβ peptide. Its clearance by the immune system prevents the cognitive decline featuring this disease.
These two antibodies represent the first disease-modifying drugs for the treatment of AD, so the good news is that finally there are available tools to stop, and in some cases even partially revert, this devastating condition. However, a frequent and characteristic side-effect of these drugs is the occurrence of brain haemorrhages, detectable by Magnetic Resonance Imaging (MRI). It is important to note that the brain is depleted of the molecules and cells building the systemic immune system, hence the entrance of antibodies in the brain is not convenient in health conditions, although necessary for these treatments to be effective. The incidence of haemorrhages in clinical trials for lecanemab and donanemab ranged from 10 to 27% of the treated patients, with especially high incidence in individuals carrying a specific allele for an apolipoprotein (APOEε4). In Europe, these treatments can only be administered to people with one or no copies of the APOEε4 allele.
Our group, led by Full Professor Sandra Villegas, has long hypothesized that full-length antibodies may be unsafe for treating neurodegenerative diseases because they drag cells from the systemic immune system into the brain. This undesirable recruitment can lead to leakage of the Blood Brain Barrier and subsequent haemorrhages. Accordingly, we designed an antibody fragment directed against the Aβ peptide but lacking the region responsible of recruiting those immune cells, specifically a single-chain antibody fragment (scFv-h3D6), and extensively demonstrated its efficiency at the molecular, cellular and cognitive levels in a mouse model of AD (3xTg-AD).
Now, in collaboration with Dr. Lope-Piedrafita (MRI expert) and Dr. Hernández-Guillamon (expert on the APP23 mouse model used), we have used MRI to visualize the haemorrhages caused by the full-length antibody bapineuzumab, from which scFv-h3D6 derives, and, noticeably, they also demonstrated that these haemorrhages do not occur when using the antibody fragment. Therefore, the contribution of this work, showing that antibody fragments may offer a safer alternative to full-length antibodies, opens an exciting window in the search for an effective and safe drug for Alzheimer’s disease.
References
Lope-Piedrafita, S., Serra-Mir, G., Melón, P., Bonaterra, A., Hernández-Guillamon, M., & Villegas, S. (2025). ScFv-h3D6 Prevents Bapineuzumab-Induced Hemorrhagic Events in the APP23 Mouse Model of Alzheimer’s Disease. Biomolecules, 15(11), 1602. https://doi.org/10.3390/biom15111602.
