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

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-beta oligomer (oA beta)-lipid microglial phagocytosis by more than 100-fold. Ab2 TVD-Ig treatment also augmented both microglia migration toward oA beta and microglia survival by 100-fold over the bivalent IgG antibody. By targeting the transferrin receptor (TfR), the brain-penetrating Ab2 TVD-Ig/alpha TfR bispecific antibody realized broad brain parenchyma distribution with a 10-fold increase in brain antibody concentration. Ab2 TVD-Ig/alpha TfR treatment of 5-month-old 5XFAD mice significantly boosted microglia-plaque interactions and enhanced amyloid plaque phagocytosis by microglia. Thus, potent TREM2 activation by a multivalent agonist antibody coupled with TfR-mediated brain entry can boost microglia clearance of amyloid plaques, which suggests the antibody has potential as an AD treatment.

Automated summary

This study engineered a bispecific antibody that can activate TREM2 and enter the brain, improving microglia clearance of amyloid plaques. The research suggests the potential of this antibody as a treatment for Alzheimer's disease.