P4–282: A multimodal imaging study of mAb158, a murine monoclonal antibody with high selectivity for amyloid protofibrils, in Tg2576 mice

mAb158 is a murine monoclonal antibody with high affinity for amyloid protofibrils. BAN2401 is the humanized version of this antibody, currently in clinical development for Alzheimer's disease (AD). This study explore d the effects of mAb158 on brain perfusion and metabolism in aged Tg2576 mice using a multimodal imaging strategy. Approximately 19 month old Tg2576 mice were treated for 12 weeks with mAb158 (50 mg/kg, weekly, i.p.; N=20) or vehicle (N=20). The primary imaging modalities were 18 F-Fluorodeoxyglucose PET (FDG) (a measure of glucose metabolism), 99m Tc-HMPAO SPECT (a measure of cerebral perfusion),and 123 I-Iomazenil SPECT (a ligand with high affinity for central benzodiazipine receptors and a n indicator of neuronal viability). Neuroimaging measures were obtained at baseline and at 12 weeks. The primary comparison was the week 12 change from baseline between the treatment and control (vehicle) groups. A random coefficients model was used to analyze changes from baseline and the Dunnett's test was applied to control for multiple comparisons. The mAb158 group showed a significant increase in 123 I-Iomazenil concentration from baseline to week 12 in the entire brain (p<0.001), cortex and hippocampus (both p<0.0001) while the control group showed no significant changes. Compared with control, the mAb158 group showed a significant improvement in 123 I-Iomazenil uptake across multiple brain regions, particularly the cortex (44%, p=0.0012). Both treatment groups experienced significant increases in 99m Tc-HMPAO uptake in the cortex, hippocampus and thalamus; when compared with controls, the mAb158 group showed a significant increase in perfusion in the cortex (p<0.05). FDG showed significant decreases (p<0.05) in the midbrain, striatum and thalamus in controls while little change was observed in the mAb158 group. However, there were no significant regional differences between the mAb158 and the control groups. The results from this exploratory study suggest that chronic treatment with mAb158 in aged Tg2576 mice may be associated with improvements in brain perfusion and neuronal viability and together provide support that BAN2401 may be an effective agent in the treatment of AD. These results also support the utility of multimodal imaging in the preclinical evaluation of novel compounds in animal models of AD.