P1‐082: THERAPEUTICALLY EFFICACIOUS ANTI‐β‐SHEET MONOCLONAL DOES NOT INDUCE MICROHEMORRHAGES OR INFLAMMATION IN TGSWDI AD MICE WITH EXTENSIVE VASCULAR AMYLOID, INCREASING CHANCES OF SAFE TRANSLATABILITY

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We have previously demonstrated that a specific anti-β-sheet secondary structure antibody combining site (paratope) in IgM or IgG class achieves significant cognitive rescue and both Aβ and Tau pathologic oligomers reduction in a 3xTg mouse model. We have now tested the safety of the aβComAb paratope in a cerebral amyloid angiopathy (CAA) TgSwDI AD model. Two groups of 15 months old TgSwDI mice with extensive CAA deposition were used for the preclinical trial. One group was inoculated i.p. weekly for two months with 100 μg/animal of paratope GW-23B7/sterile saline (IgM) or sterile saline vehicle alone. The animals then underwent locomotor and cognitive testing followed by the brains being harvested for immunohistochemical and biochemical analysis. The GW-23B7 paratope treated group showed significant cognitive rescue compare to controls on the Barnes Maze, which correlated with a significant decrease of vascular and parenchymal Aβ amyloid and lesser number of microhemorrhages and activated glia as determined by Prussian Blue, IBA1, GFAP and CD-45 immunohistochemistry. We have shown that a paratope directed only to the β-sheet secondary structure of pathologic oligomers (aβComAb-GW-23B7-IgM) does not bind fibrillary Aβ deposits, reducing Aβ pathology by a primary sequence independent mechanism that does not induce microhemorrhages or inflammation. This aβComAb-GW-23B7-IgM, proven to reduce Aβ and tau pathology and achieve significant cognitive rescue, can be safely infused, reducing the possibility of amyloid related imaging abnormalities (ARIA) or autoimmune toxicity complications if translated to human AD clinical trials.

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