Disease modifying effects of the amyloid-beta protofibril-selective antibody mAb158 in aged Tg2576 transgenic mice

Amyloid beta (A beta) peptides, which aggregate to form neocortical plaques in Alzheimer's disease, exist in states that range from soluble monomers and oligomers/protofibrils to insoluble fibrillar amyloid. The present study evaluated the effects of mAb158, a mouse monoclonal antibody version of lecanemab that preferentially binds to soluble A beta protofibrils, in aged transgenic mice (Tg2576) with A beta pathology. Female Tg2576 mice (12 months old) received weekly intraperitoneal mAb158 (35 mg/kg) or vehicle for 4 weeks or for 18 weeks, with or without a subsequent 12-week off-treatment period. A beta protofibril levels were significantly lower in mAb158-treated animals at both 4 and 18 weeks, while longer treatment duration (18 weeks) was required to observe significantly lower A beta 42 levels in insoluble brain fractions and lower A beta plaque load. Following the off-treatment period, comparison of the vehicle- and mAb158-treated mice demonstrated that the A beta protofibril levels, insoluble A beta 42 levels and A beta plaque load remained significantly lower in mAb158-treated animals, as compared with age-matched controls. However, there was a significant increase of brain accumulation of both the A beta protofibril levels, insoluble A beta 42 levels and A beta plaque load after treatment cessation. Thus, repeated mAb158 treatment of aged Tg2576 mice first reduced A beta protofibril levels within 4 weeks of treatment, which then was followed by a reduction of amyloid plaque pathology within 18 weeks of treatment. These effects were maintained 12 weeks after the final dose, indicating that mAb158 had a disease-modifying effect on the A beta pathology in this mouse model. In addition, brain accumulation of both A beta protofibril levels and amyloid pathology progressed after discontinuation of the treatment which supports the importance of continued treatment with mAb158 to maintain the effects on A beta pathology.