Discovery and engineering of an anti-TREM2 antibody to promote amyloid plaque clearance by microglia in 5XFAD mice.

ABSTRACT: Triggering receptor expressed on myeloid cells 2 (TREM2) plays a crucial role in regulating microglial functions and removal of amyloid plaques in Alzheimer's disease (AD). However, therapeutics based on this knowledge have not been developed due to the low antibody brain penetration and weak TREM2 activation. In this study, we engineered a TREM2 bispecific antibody to potently activate TREM2 and enter the brain. To boost TREM2 activation, we increased the valency of bivalent anti-TREM2 Ab2 IgG to tetra-variable domain immunoglobulin (TVD-Ig), thus improving the EC₅₀ of amyloid-β oligomer (oAβ)-lipid microglial phagocytosis by more than 100-fold. Ab2 TVD-Ig treatment also augmented both microglia migration toward oAβ and microglia survival by 100-fold over the bivalent IgG antib

SUBMITTER: Zhao P 

PROVIDER: S-EPMC9354770 | biostudies-literature | 2022 Jan-Dec

REPOSITORIES: biostudies-literature