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AC IMMUNE SA filed this Form 20-F on 03/21/2019
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Figure 13: Microglia phagocytosis by crenezumab

 

 

Ref: Adolfsson, et. al., J. Neurosci 2012

 

The Abeta oligomers complexed to crenezumab (MABT), as detailed above, are efficiently phagocytosed by microglia. Representative images show antibody-mediated phagocytosis of Abeta oligomers by microglia (A), and quantification of Abeta oligomer uptake (B). Crenezumab MABT is crenezumab; MABT-IgG1 is IgG1 backbone variant of crenezumab; and MABT-IgG1-D265A IgG1 is a backbone variant of crenezumab carrying the D265A mutation reducing the Ab-FcγR interaction of an IgG1 backbone.

 

The phagocytic clearance of Abeta oligomers may not confer benefits if it results in over-activation of neuroinflammatory events. Comparing the ability of crenezumab IgG1 and IgG4 backbone variants in reversing Abeta oligomer cytotoxicity in mixed primary cortical cultures revealed that crenezumab with the IgG1 backbone, and bearing greater FcγR binding affinity compared with the IgG4 backbone, trended toward a smaller protective effect (Adolfsson et al., 2012). The enhanced binding of the IgG1 backbone to FcγRs compared with that of IgG4 activates increased release of pro-inflammatory cytokines resulting from undesired microglia activation, likely translating into reduced protection against Abeta oligomer-mediated neurotoxicity.

 

Figure 14: Crenezumab’s IgG4 backbone balances efficacy with safety

 

 

Data reported in Adolfsson, et. al., J. Neurosci 2012

 

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