ScFv-h3D6 Prevents Bapineuzumab-Induced Hemorrhagic Events in the APP23 Mouse Model of Alzheimer's Disease
Lope-Piedrafita, Silvia (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Serra Mir, Gabriel (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Melón bajo, Paula (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Bonaterra-Pastra, Anna (Vall d'Hebron Institut de Recerca (VHIR))
Hernandez Guillamon, Maria Mar (Vall d'Hebron Institut de Recerca (VHIR))
Villegas Hernández, Sandra (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Universitat Autònoma de Barcelona. Servei de Ressonància Magnètica Nuclear

Data:	2025
Resum:	The occurrence of amyloid-related imaging abnormalities (ARIAs), found in clinical trials for Aβ-immunotherapy, has been related to the antibody's effector function on glial activation by the Fc portion of the antibody. The use of single-chain variable fragments (scFv) has been proposed as a safer therapeutic strategy. Here, the effects of the mice format of bapineuzumap (mAb-m3D6) and its scFv (scFv-h3D6) on the occurrence of ARIAs in the APP23 mouse model of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) have been addressed by magnetic resonance imaging (MRI). Results are supported by histological and/or biochemical determinations. Aged APP23 mice showed a significantly higher number of microhemorrhages than non-transgenic mice. mAb-m3D6 produced an increase in the number of new hemorrhagic events, mainly in the cortex, whereas scFv-h3D6 did not. Both mAb-m3D6 and scFv-h3D6 reduced Aβ levels by the same extent. Axonal/myelin damage was found in the frontal corpus callosum of APP23 mice, which did not recover after treatment. In conclusion, the scFv-h3D6 format appears safer than the full-length mAb in the APP23 model of AD and CAA. This finding is highly relevant in light of the new FDA- and EMA-approved mAbs, which exclude APOEε4 allele carriers due to the occurrence of hemorrhages.
Ajuts:	Agencia Estatal de Investigación SAF2017-89613R Instituto de Salud Carlos III PI17-00275
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Alzheimer's disease; amyloid-related imaging abnormalities ; Cerebral amyloid angiopathy ; Immunotherapy ; Magnetic resonance imaging ; Single-chain variable fragment
Publicat a:	Biomolecules, Vol. 15, Num. 11 (November 2025) , art. 1602, ISSN 2218-273X

DOI: 10.3390/biom15111602
PMID: 41301520

24 p, 2.2 MB

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