Antibody Fragment Eliminates Brain Haemorrhage Risk in Alzheimer's Immunotherapy, Preclinical Study Shows
核心洞察
Two recently EMA-approved Alzheimer's antibodies, lecanemab and donanemab, cause cerebral bleeding in 10–27% of treated patients, particularly in APOEε4 (搜索) carriers.
UAB researchers designed an antibody fragment (scFv-h3D6) that targets the Aβ peptide (搜索) without recruiting systemic immune cells into the brain.
MRI studies in the APP23 mouse model demonstrate that scFv-h3D6 avoids the haemorrhagic events caused by the full-length antibody bapineuzumab while maintaining therapeutic effects.
A research team at the Universitat Autònoma de Barcelona (UAB) has demonstrated that a single-chain antibody fragment targeting the amyloid-β (Aβ) peptide can avoid the cerebral haemorrhages that represent a significant safety concern with currently approved Alzheimer's disease (搜索) immunotherapies. The findings, published in Biomolecules, provide preclinical evidence that antibody fragments may offer a safer therapeutic alternative to full-length antibodies for neurodegenerative disease.
The study, led by Professor Sandra Villegas of the UAB Department of Biochemistry and Molecular Biology, used magnetic resonance imaging (MRI) to compare haemorrhagic events induced by the full-length antibody bapineuzumab with those of its derived fragment, scFv-h3D6, in the APP23 mouse model of Alzheimer's disease (搜索).
A Critical Safety Concern with Approved Therapies
In 2025, the European Medicines Agency (EMA) approved two antibodies for the treatment of Alzheimer's disease (搜索): lecanemab (Leqembi™, Biogen) and donanemab (Kisunla™, Eli Lilly and Co (搜索)). These represent the first disease-modifying therapies for Alzheimer's, capable of stopping and, in some cases, partially reversing cognitive decline by clearing Aβ peptide (搜索) aggregates from the brain.
However, a frequent and characteristic side effect of these treatments is cerebral bleeding, detectable by MRI. Clinical trial data indicate that the incidence of haemorrhages ranged from 10% to 27% of treated patients, with a particularly high incidence in individuals carrying the APOEε4 (搜索) allele—a genetic variant associated with elevated Alzheimer's risk. In Europe, these treatments are restricted to patients with one or no copies of the APOEε4 allele.
The Hypothesis: Immune Cell Recruitment as a Culprit
Professor Villegas and her group have long hypothesised that full-length antibodies may be inherently unsafe for treating neurodegenerative diseases because they recruit cells from the systemic immune system into the brain. The brain is normally depleted of the molecules and cells that constitute the systemic immune system, and this undesirable recruitment can disrupt the blood-brain barrier, leading to leakage and subsequent haemorrhages.
To address this, the team designed scFv-h3D6, a single-chain antibody fragment directed against the Aβ peptide (搜索) that lacks the region responsible for recruiting immune cells. The fragment's efficacy had previously been demonstrated at the molecular, cellular, and cognitive levels in the 3xTg-AD mouse model of Alzheimer's disease (搜索).
MRI Evidence from the APP23 Mouse Model
In the current study, conducted in collaboration with Dr. Silvia Lope-Piedrafita, an MRI expert at UAB, and Dr. Mar Hernández-Guillamon, a researcher at the Vall d'Hebron Research Institute and expert in the APP23 mouse model, the team used MRI to visualise haemorrhages caused by bapineuzumab—the full-length antibody from which scFv-h3D6 derives—and compared them with the effects of administering only the antibody fragment.
The results showed that the haemorrhagic events observed with bapineuzumab did not occur when the antibody fragment was administered, while therapeutic effects were maintained.
"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 (搜索)," said Professor Villegas.
The original research article, titled "ScFv-h3D6 Prevents Bapineuzumab-Induced Hemorrhagic Events in the APP23 Mouse Model of Alzheimer's Disease (搜索)," was published by Lope-Piedrafita, S., Serra-Mir, G., Melón, P., Bonaterra, A., Hernández-Guillamon, M., & Villegas, S. in Biomolecules, 15(11), 1602.