Characterization of the selective in vivo and in vitro binding properties of crenezumab: insights into crenezumab’s unique mechanism of action

Identification: Meilandt, William


Description

Characterization of the selective in vivo and in vitro binding properties of crenezumab: insights into crenezumab's unique mechanism of action
 
William J. Meilandt1, Janice A. Maloney1, Jose Imperio1, Travis W. Bainbridge2, Guita Lalehzadeh1, Mike Reichelt3, Danielle Mandikian4, Yanmei Lu5, James A. Ernst2, Reina N. Fuji6, Jasvinder K. Atwal1
Department of Neuroscience1, Protein Sciences2, Research Pathology3, Preclinical and Translational Pharmacology4, Biochemical and Cellular Pharmacology5, Safety Assessment6, Genentech, South San Francisco, CA, USA
 
Crenezumab is a monoclonal anti-amyloid beta (Aβ) immunoglobulin G4 (IgG4) antibody that is currently being developed for the treatment of Alzheimer's disease (AD). Crenezumab binds to monomeric as well as aggregated forms of Aβ in vitro, with high affinity to Aβ oligomers, the form of Aβ hypothesized to mediate neurotoxicity in AD. Here, 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 at various dose levels. Using immunoprecipitation (IP) and Western blotting analysis, we also evaluated the interaction between crenezumab and different forms of synthetic Aβ oligomers and native Aβ isolated from soluble brain homogenates from the PS2APP mouse model of AD.  In vivo studies show that crenezumab, but not a control antibody, binds to brain regions in the PS2APP mice that are enriched in oligomeric Aβ including the periphery of amyloid plaques and to the mossy-fiber axons in an age and dose-dependent manner. Crenezumab binding was also enriched at dystrophic neurites surrounding plaques. No crenezumab binding was observed in non-transgenic mice, or in PS2APPxBACE1ko/ko mice, suggesting that this binding was Aβ-dependent. Electron microscopy was performed to gain ultrastructure resolution of the brain regions that showed crenezumab binding. It was also noted that crenezumab does not bind to vascular amyloid at the dose levels evaluated. In vitro, crenezumab is able to IP oligomeric Aβ from synthetic preparations, and IP a mixture of different Aβ forms including dimers from soluble brain homogenates prepared from PS2APP mice. These results demonstrate crenezumab's preferential in vivo and in vitro binding to Aβ oligomers; the form of Aβ hypothesized to mediate neurotoxicity in AD, and supports the clinical rationale for crenezumab as a potential treatment for AD.
 

Credits

Credits: None available.

You must be logged in and own this product in order to post comments.