Characterization of the Selective In Vivo and In Vitro Binding Properties of Crenezumab: Insights into Crenezumab’s Unique Mechanism of Action (P6.174)

Objective: To better understand crenezumab’s mode of action by investigating its binding to endogenous amyloid-beta (Aβ) in the PS2APP transgenic model of Alzheimer’s disease (AD). Background: Crenezumab is a monoclonal anti-Aβ immunoglobulin G4 (IgG4) antibody being developed for the treatment of AD. Crenezumab binds to monomeric as well as aggregated forms of Aβ in vitro , with high affinity to Aβ oligomers, the form hypothesized to mediate neurotoxicity in AD. We investigated the binding characteristics of crenezumab to endogenous Aβ in vivo in a mouse model of AD, as well as to various forms of synthetic or native Aβ oligomers in vitro . Design/Methods: We characterized the in vivo binding pattern of crenezumab to Aβ in brains of PS2APP mice by immunohistochemistry and electron microscopy following a single intravenous injection. Using immunoprecipitation and Western blotting, we also evaluated the interaction between crenezumab and different forms of synthetic or native Aβ. Results: In vivo studies show that crenezumab binds specifically to brain regions in the PS2APP mice that are hypothesized to be enriched in Aβ oligomers, including the periphery of amyloid plaques and the hippocampal mossy-fiber axons. Electron microscopy was performed to gain ultrastructure resolution of crenezumab binding. Crenezumab did not bind to vascular amyloid. In vitro , crenezumab immunoprecipitates Aβ oligomers from different synthetic preparations and a mixture of soluble Aβ forms, including oligomers, from PS2APP mouse brain homogenates. Conclusions: Crenezumab’s preferential in vivo and in vitro binding to Aβ oligomers, the form of Aβ hypothesized to mediate neurotoxicity in AD, supports its unique mechanism of action as a potential treatment for AD. The lack of binding to vascular amyloid in our mouse model of AD, in addition to the reduced effector function on the IgG4 backbone, may explain crenezumab’s low risk of amyloid related imaging abnormalities observed in clinical trials to date. Disclosure: Dr. Meilandt has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Maloney has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Imperio has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Bainbridge has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Reichelt has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Mandikian has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Lu has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Ernst has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Fuji has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Atwal has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech.