ScFv-h3D6 Prevents Bapineuzumab-Induced Hemorrhagic Events in the APP23 Mouse Model of Alzheimer’s Disease

The occurrence of amyloid-related imaging abnormalities (ARIA), 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, effects of the mice format of bapineuzumap (mAb-m3D6) and its scFv (scFv-h3D6) on the occurrence of ARIA in the APP23 mouse, a model of Alzheimer 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 to the same extent. Axonal/myelin damage was found in the frontal corpus callosum of APP23 mice and not recovered by treatments. To sum up, the scFv-h3D6 format appears safer than full-length mAb in the APP23 model of AD and CAA. This finding is highly relevant in the light of the new FDA- and EMA-approved mAbs, which exclude APOEε4 allele carriers due to the occurrence of hemorrhages.