Deglycosylation of anti-ß amyloid antibodies inhibits microglia activation in BV-2 cellular model

Abstract

Immunotherapy has become a strategy for treatment of Alzheimer's disease, by inducing antibody response to amyloid-beta peptide (AbetaP) or by passive administration of anti-AbetaP antibodies. Clearance of amyloid plaques involves interaction of immunoglobulin Fc receptor (FcR)-expressing microglia and antibodyopsonized Abeta deposits, stimulating phagocytosis but may promote neuroinflammation. Carbohydrate moiety of Fc of the immunoglobulin G molecule plays a significant role in modulating binding to FcR and its effector functions. Here, we enzymatically removed Fc glycan from monoclonal antibody 196 raised against AbetaP Antigen binding ability and in vitro stability of deglycosylated antibody were unaffected by deglycosylation. Moreover, the deglycosylated antibody exhibits low affinity to FcR on microglial BV-2 cells and has limited ability to mediate microglial chemotaxis and antibodydependent cytotoxicity compared to native antibody. These data suggest that deglycosylation of anti-Abeta antibodies before in vivo administration might prevent microglial overactivation, thus reducing the risk of neuroinflammatory response during passive immunization.

Deglycosylated anti‐amyloid beta antibodies reduce microglial phagocytosis and cytokine production while retaining the capacity to induce amyloid beta sequestration

“…Deglycosylated antibodies showed limited ability to activate immortalized microglia, BV-2, in vitro (Rebe & Solomon, 2005). In addition, chronic treatment with deglycosylated antibody against the C terminus of Abeta 40, in comparison with intact antibody, is associated with reduced accumulation of CD45-immunopositive activated microglia surrounding plaques and improved cognitive performance in an AD model mouse in vivo (Carty et al, 2006;Wilcock et al, 2006).…”

Immune recruitment or suppression by glycan engineering of endogenous and therapeutic antibodies

“…Despite being effective, systemic administration of anti-Aβ antibodies using unmodified IgG can provoke neuroinflammation via microglial activation and thus increases the risk of vascular amyloid and brain microhemorrhage [156] , [157] , [158] . In contrast, deglycosylated anti-Aβ antibodies greatly reduce such incidents while still retaining the properties of cognition-enhancing and amyloid sequestration [159] , [160] , [161] , [162] . In another study, deglycosylation has been shown to convert pathogenic neuromyelitis optica (NMO)-IgG autoantibodies into therapeutic blocking antibodies [163] .…”