Figure 13: Microglia phagocytosis by
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.