LAUSR

Triggering receptor expressed on myeloid cells 2 (TREM2) plays crucial roles in Alzheimer’s disease (AD) by regulating microglia migration toward, and phagocytosis of oligomeric amyloid-β (oAβ) and amyloid plaques. Studies in rodent models of AD have shown that mice with increased TREM2 expression have reduced amyloid pathology. Here, we identified a TREM2 agonist monoclonal Ab (Ab18) by panning a phage-displayed single-chain variable fragment Ab library. By engineering the bivalent immunoglobulin G1 (IgG1) to tetra-variable domain immunoglobulin (TVD-Ig), we further increased the TREM2 activation by 100-fold. Stronger TREM2 activation led to enhanced microglia phagocytosis of the oAβ-lipid complex, migration toward oAβ, and improved microglia survival in vitro. Mechanistic studies showed increased TREM2 clustering on microglia by the tetravalent Ab18 TVD-Ig without altering microglial TREM2 amount. An engineered bispecific Ab targeting TREM2 and transferrin receptor (TfR; Ab18 TVD-Ig/αTfR) improved Ab brain entry by more than 10-fold with a broad brain parenchyma distribution. Weekly treatment of 5XFAD mice (a model of AD) with Ab18 TVD-Ig/αTfR showed a considerable reduction of amyloid burden with increased microglia migration to and phagocytosis of amyloid plaques, improved synaptic and neuronal marker intensity, improved cognitive functions, reduced endogenous tau hyperphosphorylation, and decreased phosphorylated neurofilament H immunostaining. This study demonstrated the feasibility of engineering multivalent TREM2 agonistic Ab coupled with TfR-mediated brain delivery to enhance microglia functions and reduce amyloid pathology in vitro and in vivo. This Ab engineering approach enables the development of effective TREM2-targeting therapies for AD. Description Tetra-variable domain TREM2 agonistic Ab reduces amyloid burden, ameliorate neuron damage, and alleviate cognitive decline in a model of AD. Leveraging immunity for TREM2 activation The receptor TREM2 has been shown to play an important role in the pathophysiology of Alzheimer’s disease (AD), and recent data suggest that increasing TREM2 activation could have therapeutic effects. Here, Zhao et al. developed a TREM2 agonistic Ab that strongly increased TREM2 activation and promoted Aβ oligomers phagocytosis and microglia survival in coculture experiments. By engineering the Ab, the authors increased its potency and improved brain penetrance. In vivo treatment in a mouse model of AD had therapeutic effects, including increased microglia-mediated phagocytosis and improved cognition, among other effects. The results suggest that Ab-mediated TREM2-targeting therapies might be effective in reducing AD pathology.