A tetravalent TREM2 agonistic antibody reduced amyloid pathology in a mouse model of Alzheimer’s disease

Abstract

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.

The neuroimmune axis of Alzheimer’s disease

“…The association between Alzheimer’s β-amyloid deposition and sTREM2 [ 316 ] points to the notion that one can leverage treatments of microglia-modulating and anti-amyloid therapeutics by targeting, e.g., TREM2 or CD33 . Recent studies showed the promising effects of increasing TREM2 in a mouse model using an agonistic antibody design [ 317 ]. However, the temporal component is crucial and a beneficial effect of increasing TREM2 is observed, especially in the early stage of AD development, highlighting the dynamic role of TREM2 in modulating β-amyloid deposition and neuritic dystrophy in AD pathogenesis [ 317 , 318 ].…”

TREM2 dependent and independent functions of microglia in Alzheimer’s disease

“…Therefore, engineered antibodies hold great promise to treat AD. A bispecific antibody consisting of a tetravalent TREM2-targeting antibody and an antibody targeting the mouse transferrin receptor (TREM2/αTfR bispecific Ab) has been developed, which strongly facilitates brain delivery and increases microglial TREM2 activation [210]. It is noteworthy that contrasting effects of TREM2 activation have been reported in different AD pathologies and disease stages, suggesting TREM2 activation may be beneficial in a certain time window and in Aβ pathology rather than tau pathology.…”

S-BEAM: A Semi-Supervised Ensemble Approach to Rank Potential Causal Variants and Their Target Genes in Microglia for Alzheimer’s Disease

“…Research has found that CELF1 is involved in the regulation of alternative splicing for exon 3 of the TREM2 locus (Yanaizu et al, 2020), which serves to make a triggering receptor protein that plays crucial roles in AD pathophysiology. TREM2 regulates microglial migration toward and phagocytosis of amyloid-beta plaques and studies in rodent models have shown that increased TREM2 expression has reduced amyloid pathology (Zhao et al, 2022). This evidence is further supported given that CELF1 expression is enriched within microglia.…”